Benzoylation Methods

Schotten-Baumann Reaction. In the Schotten-Baumann method of benzoylation, the hydroxyl or amino compound (or a salt of the latter) is either suspended or dissolved in an excess of freshly prepared 10% (w/v) aqueous sodium hydroxide solution, together with a small excess of benzoyl chloride ii.e., nearly 10% more than the theoretical quantity), and the resulting mixture is shaken vigorously in ambient conditions. It has been observed that under these experimental parameters benzoylation proceeds smoothly. Thus, the solid benzoylated product, which being insoluble in the aqueous medium, gets separated briskly. Simultaneously, the NaOH solution hydrolyses the excess of benzoyl chloride present in reaction mixture, thereby resulting into the formation of sodium chloride and sodium benzoate, which being water-soluble remain in solution. 

The various reactions that are involved in the Schotten-Baumann method of benzoylation are as given below  

Equation (a) Phenol first undergoes dissolution in sodium hydroxide solution to result into the formation of sodium phenoxide, which on being subjected to benzoylation yields phenyl benzoate. 

Equation (6) Likewise, aniline i.e., a primary aiyl amine, gives rise to the formation of benzanilide or phenyl benzamide or benzoyl aniline as the final product plus one mole of HCl. 

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Aldehydeless dark mutants, 35-37 effect of cyanide, 37 Aminopyrazine, 160 Ammodytes, 163 Amphipod, 47 Ampbiura, 163, 337 Amphiura fHiformis, 302, 307, 345 Ampbiura luciferase, 307, 345 Anaerobic condition, 351 Anderson s benzoylation method, 54, 55... 

Precautionary Measures. There are two cardinal precautionary measures that have to be taken into consideration while carrying out Schotten-Baumann benzoylation method, such as ... 

An efficient and ecofriendly microwave irradiated solvent-free benzoylation method was developed by Al-Masum et al. (2011). 50 mol% AICI3 was used as a Lewis aeid catalyst at 130 °C for C-benzoylation and the reaction was completed in 10 min. The isolated yield was between 71-100%. N-benzoylation was also eondueted in a catalyst-free environment at 130 °C in 10 min but the yield was between 80-100%. 

The dibenzoyl derivatives can be prepared by the normal Schotten-Baumann method, using 10% aqueous sodium hydroxide and an excess of benzoyl chloride, but the m.ps. of the dibenzoyl derivatives are inconveniently high (p- ssO-... 

The experimental technique is similar to that given under Aromatic Amines, Section IV,100,2. The following alternative method may also be used. Mix together 0 -5-0 - 8 ml. of the polyhydroxy compound, 5 ml. of pyridine and 2 -5 ml. of redistilled benzoyl chloride in a 50 ml. flask. 

Method 1. Place in a test-tube or small flask 1-3 g. of glycerol and 30 ml. of 10 per cent, sodium hydroxide solution add gradually, with simultaneous shaking, 1-2 g. of benzoyl chloride. Stopper the vessel, shake for several minutes and allow to stand. Decant the solution from the pasty solid and wash the latter with cold water by decantation. Recrystallise the solid tribenzoate from dilute rectified (or methylated) spirit or from light petroleum, b.p. 40-60° the pure compound has m.p. 76°. 

Method 2. Add gradually 2 -5 ml. of benzoyl chloride to a solution of 0-5 g. of glycerol in 5 ml. of pure pyridine, cooled in ice then reflux for 1 hour. Treat the cold mixture with dilute sulphuric acid this dissolves the pyridine salt and precipitates the glycerol tribenzoate. Wash it with sodium bicarbonate solution, followed by water, and recrystaUise as in Method 1. 

Trimethylene dibromide (Section 111,35) is easily prepared from commercial trimethj lene glycol, whilst hexamethylene dibromide (1 O dibromohexane) is obtained by the red P - Br reaction upon the glycol 1 6-hexanediol is prepared by the reduction of diethyl adipate (sodium and alcohol lithium aluminium hydride or copper-chromium oxide and hydrogen under pressure). Penta-methylene dibromide (1 5-dibromopentane) is readily produced by the red P-Brj method from the commercially available 1 5 pentanediol or tetra-hydropyran (Section 111,37). Pentamethylene dibromide is also formed by the action of phosphorus pentabromide upon benzoyl piperidine (I) (from benzoyl chloride and piperidine) ... 

In general, benzoylation of aromatic amines finds less application than acetylation in preparative work, but the process is often employed for the identification and characterisation of aromatic amines (and also of hydroxy compounds). Benzoyl chloride (Section IV, 185) is the reagent commonly used. This reagent is so slowly hydrolysed by water that benzoylation can be carried out in an aqueous medium. In the Schotten-Baumann method of benzoylation the amino compound or its salt is dissolved or suspended in a slight excess of 8-15 per cent, sodium hydroxide solution, a small excess (about 10-15 per cent, more than the theoretical quantity) of benzoyl chloride is then added and the mixture vigorously shaken in a stoppered vessel (or else the mixture is stirred mechanically). Benzoylation proceeds smoothly and the sparingly soluble benzoyl derivative usually separates as a solid. The sodium hydroxide hydrolyses the excess of benzoyl chloride, yielding sodium benzoate and sodium chloride, which remain in solution ... 

The Schotten - Baumann method of benzoylation with benzoyl chloride in the presence of aqueous sodium hydroxide may be used. Full details are given under Amines Section IV.lOO, 2. 

Method 2. Into a 500 ml. round-bottomed flask place 120 ml. of dry A.R. benzene, and 35 g. (29 ml.) of redistilled benzoyl chloride. Weigh out 30 g. of finely-powdered, anhydrous aluminium chloride into a dry corked test-tube, and add the solid, with frequent shaking, during 10 minutes to the contents of the flask. Fit a reflux condenser to the flask, and heat on a water bath for 3 hours or until hydrogen chloride is no longer evolved. Pour the contents of the flask wliile still warm into a mixture of 200 g. of crushed ice and 100 ml. of concentrated hydrochloric acid. Separate the upper benzene layer (filter first, if necessary), wash it with 50 ml. of 5 per cent, sodium hydroxide solution, then with water, and dry with anhydrous magnesium sulphate. Isolate the benzophenone as in Method 1. The yield is 30 g. 

The advantage of this method is that it avoids the use of hydrogen selenide, necessary for the preparation of selenourea from cyanamide (14). Benzoylselenourea is synthesized by the method of Douglass (24) by the action of potassium selenocyanate On benzoyl chloride in acetone solution. 

N-benzoyl derivatives of o -aminoacids give 2-phenyl-5-alkoxythiazoles (64). A list of the thiazoles prepared by this method is given in Table 11-32 (711). 

PMMA-impregnated sol—gel-derived siUca gels have also been examined (54). Long-wave uv illumination was employed in addition to benzoyl peroxide for PMMA polymerization. This method prohibited the degradation of the siUca xerogel from moisture adsorption and desorption. Overall the material behaved more like bulk PMMA than bulk siUca, with the exception of hardness. 

More useful than the preceding methods is cleavage of alkoxides by acetyl chloride or bromide. One, two, three, or four alkoxyls can be replaced by chloride or bromide. Benzoyl chloride gives poor yields, however. The tri- and tetrachlorides, which are stronger Lewis acids than mono- and dichlorides, coordinate with the alkyl acetate formed and yield distillable complexes (46,55,56). 

Friedel-Crafts Acylation. The Friedel-Crafts acylation procedure is the most important method for preparing aromatic ketones and thein derivatives. Acetyl chloride (acetic anhydride) reacts with benzene ia the presence of aluminum chloride or acid catalysts to produce acetophenone [98-86-2], CgHgO (1-phenylethanone). Benzene can also be condensed with dicarboxyHc acid anhydrides to yield benzoyl derivatives of carboxyHc acids. These benzoyl derivatives are often used for constmcting polycycHc molecules (Haworth reaction). For example, benzene reacts with succinic anhydride ia the presence of aluminum chloride to produce P-benzoylpropionic acid [2051-95-8] which is converted iato a-tetralone [529-34-0] (30). 

The procedures as outlined are applicable to both the aliphatic and aromatic series. They are superior to the common interchange method in that they avoid the fractional distillation which is very troublesome in the aliphatic series. They have been used in numerous instances and can be adapted to give mixed anli3"drides. Benzoic anhydride has been obtained, by closely related procedures, from benzoic acid and benzoyl chloride by heating under reduced pressure or in the presence of zinc chloride. 

The ethyl 7-veratrylbutyrate, b.p. 203-207°/20 mm., is obtained in 80% yield by esterification of 7-veratrylbutyric acid by the Fischer-Speier method. The 7-veratrylbutyric acid is prepared by the method of E. L. Martin from /3-(3,4-dimethoxy-benzoyl)-propionic acid. 

Bromelain (anti-inflammatory Ananase from pineapple) [37189-34-7] Mr 33 000, [EC 3.4.33.4]. This protease has been purified via the acetone powder, G-75 Sephadex gel filtration and Bio-Rex 70 ion-exchange chromatography and has Aj 20.1 at 280nm. The protease from pineapple hydrolyses benzoyl glycine ethyl ester with a Km (app) of 210mM and kcat of 0.36 sec. [Murachi Methods Enzymol 19 273 1970 Balls et al. nd Eng Chem 33 950 1941.]... 

This method is an adaptation of that of Dengel. -Methoxy-phenylacetonitrile can also be prepared by the metathetical reaction of anisyl chloride with alkali cyanides in a variety of aqueous solvent mixtures by the nitration of phenylaceto-nitrile, followed by reduction, diazotization, hydrolysis, and methylation 1 by the reduction of ct-benzoxy- -methoxy-phenylacetonitrile (prepared from anisaldehyde, sodium cyanide, and benzoyl chloride) and by the reaction of acetic anhydride with the oxime of -methoxyphenylpyruvic acid. ... 

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